Cyclic-3′,5′-adenosine monophosphate (cAMP) mediates cellular responses to nutritional conditions and extracellular conditions in organisms from bacteria to humans. Cyclic AMP is synthesized from adenosine triphosphate (ATP) by adenylyl cyclase, and it is rapidly destroyed by cyclic AMP phosphodiesterases that hydrolyze cAMP to form adenosine 5′-monophosphate (5′-AMP). In a non-responding cell, a basal level of cAMP synthesis is balanced by the rate of its breakdown. The concentration of cyclic AMP inside a cell can change by more than twenty fold in seconds in response to extracellular signals. These rapid responses arise because the activity of the adenylyl cyclase is stimulated such that synthesis of the molecule overwhelms this normal (usually static) rate of breakdown.
Adenylyl cyclase is a group of enzymes that catalyze the conversion of ATP to cAMP and pyrophosphate. Six classes of adenylyl cyclase enzymes have been identified based upon protein sequence and properties. Class I adenylyl cyclases are found primarily in enteric bacteria. Class II adenylyl cyclases include the toxins secreted by pathogens such as edema factor (EF) from Bacillus anthracis (which causes anthrax), CyaA from Bordetella pertussis (the cause of whooping cough), and ExoY from Pseudomonas aeruginosa (the cause of various nosocomial infections). Class III is the largest known group and consists of cyclases found in bacteria, archaea and eukaryotes. The class IV enzymes are found in archaeal organisms, and also in some bacteria including the plague-causing Yersinia pestis. Class V is comprised of adenylyl cyclase from the strict anaerobic bacterium Prevotella ruminicola. Class VI is found in the nitrogen fixing bacteria Rhizobium etli. All six classes of enzymes are present in bacteria, while only enzymes belonging to class III have been described in eukaryotes.
In mammalian cells, cAMP is produced by two related families of class III adenylyl cyclase, transmembrane adenylyl cyclases (tmAC) and soluble adenylyl cyclases (sAC). These two families differ in sub-cellular localization, and respond to different regulators (for a review see Kamenetsky et al., J. Mol. Biol. Vol. 362, pp. 623-39, 2006). The primary regulators for tmACs are hetrotrimeric G proteins, which transmit extracellular signals via G protein-coupled receptors in response to hormonal stimuli. In contrast, sACs are regulated by intracellular bicarbonate and calcium.
In bacteria, adenylyl cyclase generates cAMP in response to characteristics of the local environment. For example, in the bacteria, Escherichia coli, cAMP levels are associated with the nutritional environment surrounding the bacteria. In an environment with plentiful glucose, cAMP levels are at their lower, non-stimulated level. When energy sources are limiting, there is a significant increase in intracellular cAMP levels.
During pathogenesis in a host, an infecting bacteria is challenged to respond to a diverse and dynamic set of environmental conditions. A variety of pathogens exploit this dramatic environmental shift as a signal to alter their growth and virulence. For example, there is a 150-fold difference in CO2 concentration inside the human (or animal) body (5% CO2) compared to the atmosphere (0.03% CO2). When infectious micro-organisms sense this difference, they tailor their genetic program to one most suitable for being inside an infectible host.
Bacteria that are resistant to one or more antibiotics, which make some diseases particularly hard to control, have become increasingly widespread. In fact, virtually all significant bacterial infections in the world are becoming resistant to the current antibiotic treatment of choice. Diseases such as tuberculosis, gonorrhea, malaria, and childhood ear infections are now more difficult to treat than they were just a few decades ago. Drug resistance is an especially difficult problem in clinical settings, such as hospitals. Thus, in the ongoing endeavor to prevent and treat infection by bacteria, there is a great need for novel methods for treating and preventing infection by bacteria.